tbuckley/cabot-search huggingface dataset:
Genomic Sequencing as a First-Tier Screening Test and Outcomes of Newborn Screening
Authors: Ting Chen, Chunna Fan, Yonglan Huang, Jizhen Feng, Yinhong Zhang, Jingkun Miao, Xiaohua Wang, Yulin Li, Cidan Huang, Weiwei Jin, Chengfang Tang, Lulu Feng, Yifan Yin, Bo Zhu, Meng Sun, Xiulian Liu, Jiale Xiang, Minyi Tan, Liyun Jia, Lei Chen, Hui Huang, Huanhuan Peng, Xin Sun, Xuefan Gu, Zhiyu Peng, Baosheng Zhu, Hui Zou, Lianshu Han
Journal: JAMA Network Open (2023)

Newborn screening via biochemical tests is in use worldwide. The availability of genetic sequencing has allowed rapid screening for a substantial number of monogenic disorders. However, the outcomes of this strategy have not been evaluated in a general newborn population.To evaluate the outcomes of applying gene panel sequencing as a first-tier newborn screening test.This cohort study included newborns who were prospectively recruited from 8 screening centers in China between February 21 and December 31, 2021. Neonates with positive results were followed up before July 5, 2022.All participants were concurrently screened using dried blood spots. The screen consisted of biochemical screening tests and a targeted gene panel sequencing test for 128 conditions. The biochemical and genomic tests could both detect 43 of the conditions, whereas the other 85 conditions were screened solely by the gene panel.The primary outcomes were the number of patients detected by gene panel sequencing but undetected by the biochemical test.This study prospectively recruited 29 601 newborns (15 357 [51.2%] male). The mean (SD) gestational age was 39.0 (1.5) weeks, and the mean (SD) birth weight was 3273 (457) g. The gene panel sequencing screened 813 infants (2.7%; 95% CI, 2.6%-2.9%) as positive. By the date of follow-up, 402 infants (1.4%; 95% CI, 1.2%-1.5%) had been diagnosed, indicating the positive predictive value was 50.4% (95% CI, 50.0%-53.9%). The gene panel sequencing identified 59 patients undetected by biochemical tests, including 20 patients affected by biochemically and genetically screened disorders and 39 patients affected by solely genetically screened disorders, which translates into 1 out of every 500 newborns (95% CI, 1/385-1/625) benefiting from the implementation of gene panels as a first-tier screening test.In this cohort study, the use of gene panel sequencing in a general newborn population as a first-tier screening test improved the detection capability of traditional screening, providing an evidence-based suggestion that it could be considered as a crucial method for first-tier screening.
p53 and Innate Immune Signaling in Development and Cancer: Insights from a Hematologic Model of Genome Instability
Authors: Christian Zierhut
Journal: Cancer Research (2023)

Abstract Genome instability due to the loss of DNA repair factors can drive developmental defects, autoinflammatory disease, and cancer. Two major signaling pathways are activated by genome instability—DNA damage checkpoint signaling, leading to p53 activation, and innate immunity, largely driven by the DNA sensor cGAS. Like p53, cGAS is thought to drive cell death and senescence during genotoxic stress in addition to its canonical inflammatory functions, but its role during cellular differentiation and carcinogenesis is poorly understood. Furthermore, it is heavily debated whether the cGAS pathway primarily has tumor-suppressive or oncogenic functions. A study in this issue of Cancer Research used a hematopoietic lineage-specific knockout of the ribonucleotide repair gene Rnaseh2b to introduce genotoxic stress, resulting in severe hematopoiesis defects and increased incidence of hematologic cancers. These two effects were driven by and antagonized by p53, respectively. Surprisingly, despite increased innate immune signaling, the cGAS pathway did not seem to play a role in either process. These findings suggest that innate immune responses to genotoxic stress may be more subtle and context-specific than appreciated, indicating that a more detailed understanding of pathway activation and signaling consequences is needed. See related article by Dressel et al., p. 2858
Addition of Group Name in Byline and Nonauthor Collaborators Supplement
Authors: Nadia Sawicki
Journal: JAMA (2023)

Rosa A. Enklaar, MD; Sascha F. M. Schulten, MD, PhD; Hugo W. F. van Eijndhoven, MD, PhD; Mirjam Weemhoff, MD, PhD; Sanne A. L. van Leijsen, MD, PhD; Marijke C. van der Weide, PhD; Jeroen van Bavel, MD; Anna C. Verkleij-Hagoort, MD, PhD; Eddy M. M. Adang, PhD; Kirsten B. Kluivers, MD, PhD; SAM Study Group; Joggem Veen; Diana Massop-Helmink; Marko Sikkema; Charlotte Lenselink; Pieternel Steures; Chantal Wingen; Kim Notten; Deliana van Rumpt-van de Geest; Jorik Vellekoop; Maria Karin Engberts; Anne Damoiseaux; Jackie Stoutjesdijk; Ronald J.C. Mouw; Marinus van der Ploeg; Iris van Gestel; Astrid Vollebregt; Jelle Stekelenburg; Wilbert Spaans; Stella Tiersma; Wenche Klerkx; Leonie Speksnijder
Structural Basis of PML-RARA Oncoprotein Targeting by Arsenic Unravels a Cysteine Rheostat Controlling PML Body Assembly and Function
Authors: Pierre Bercier, Qian Qian Wang, Ning Zang, Jie Zhang, Chang Yang, Yasen Maimaitiyiming, Majdouline Abou-Ghali, Caroline Berthier, Chengchen Wu, Michiko Niwa-Kawakita, Thassadite Dirami, Marie-Claude Geoffroy, Omar Ferhi, Samuel Quentin, Shirine Benhenda, Yasumitsu Ogra, Zoher Gueroui, Chun Zhou, Hua Naranmandura, Hugues de Thé, Valérie Lallemand-Breitenbach
Journal: Cancer Discovery (2023)

Abstract PML nuclear bodies (NB) are disrupted in PML-RARA–driven acute promyelocytic leukemia (APL). Arsenic trioxide (ATO) cures 70% of patients with APL, driving PML-RARA degradation and NB reformation. In non-APL cells, arsenic binding onto PML also amplifies NB formation. Yet, the actual molecular mechanism(s) involved remain(s) elusive. Here, we establish that PML NBs display some features of liquid–liquid phase separation and that ATO induces a gel-like transition. PML B-box-2 structure reveals an alpha helix driving B2 trimerization and positioning a cysteine trio to form an ideal arsenic-binding pocket. Altering either of the latter impedes ATO-driven NB assembly, PML sumoylation, and PML-RARA degradation, mechanistically explaining clinical ATO resistance. This B2 trimer and the C213 trio create an oxidation-sensitive rheostat that controls PML NB assembly dynamics and downstream signaling in both basal state and during stress response. These findings identify the structural basis for arsenic targeting of PML that could pave the way to novel cancer drugs. Significance: Arsenic curative effects in APL rely on PML targeting. We report a PML B-box-2 structure that drives trimer assembly, positioning a cysteine trio to form an arsenic-binding pocket, which is disrupted in resistant patients. Identification of this ROS-sensitive triad controlling PML dynamics and functions could yield novel drugs. See related commentary by Salomoni, p. 2505. This article is featured in Selected Articles from This Issue, p. 2489
Haemodynamic and metabolic phenotyping of patients with aortic stenosis and preserved ejection fraction: A specific phenotype of heart failure with preserved ejection fraction?
Authors: Nicolò De Biase, Matteo Mazzola, Lavinia Del Punta, Valerio Di Fiore, Marco De Carlo, Cristina Giannini, Giulia Costa, Francesco Paneni, Alessandro Mengozzi, Lorenzo Nesti, Luna Gargani, Stefano Masi, Nicola Riccardo Pugliese
Journal: European Journal of Heart Failure (2023)
Activation of Nod2 signaling upon norovirus infection enhances antiviral immunity and susceptibility to colitis
Authors: Ghaffar Muharram, Marion Thépaut, Pierre-Emmanuel Lobert, Teddy Grandjean, Olivier Boulard, Myriam Delacre, Emmrich Wakeford, Richard Wheeler, Lionel Franz Poulin, Ivo Gomperts Boneca, Frank Lafont, Marie-Cécile Michallet, Didier Hober, Ken Cadwell, Mathias Chamaillard
Journal: Gut Microbes (2023)

Over 90% of epidemic non-bacterial gastroenteritis are caused by human noroviruses (NoVs), which persist in a substantial subset of people allowing their spread worldwide. This has led to a significant number of endemic cases and up to 70,000 children deaths in developing countries. NoVs are primarily transmitted through the fecal-oral route. To date, studies have focused on the influence of the gut microbiota on enteric viral clearance by mucosal immunity. In this study, the use of mouse norovirus S99 (MNoV_S99) and CR6 (MNoV_CR6), two persistent strains, allowed us to provide evidence that the norovirus-induced exacerbation of colitis severity relied on bacterial sensing by nucleotide-binding oligomerization domain 2 (Nod2). Consequently, Nod2-deficient mice showed reduced levels of gravity of Dextran sodium sulfate (DSS)-induced colitis with both viral strains. And MNoV_CR6 viremia was heightened in Nod2-/- mice in comparison with animals hypomorphic for Atg16l1, which are prone to aggravated inflammation under DSS. Accordingly, the infection of macrophages derived from WT mice promoted the phosphorylation of Signal Transducer and Activator of Transcription 1 (STAT1) and NOD2's expression levels. Higher secretion of Tumor Necrosis Factor alpha (TNFα) following NOD2 activation and better viral clearance were measured in these cells. By contrast, reduced levels of pSTAT1 and blunted downstream secretion of TNFα were found in Nod2-deficient macrophages infected by MNoV_S99. Hence, our results uncover a previously unidentified virus-host-bacterial interplay that may represent a novel therapeutic target for treating noroviral origin gastroenteritis that may be linked with susceptibility to several common illnesses such as Crohn's disease.
Gluten-sensitive enteropathy in recessive dystrophic epidermolysis bullosa
Authors: Rosa Sacedón, M Carmen de Arriba, Lucía Martínez-Santamaría, Rocío Maseda, Sara Herráiz-Gil, Eva Jiménez, Isabel Rosales, Lucía Quintana, Nuria Illera, Marta García, Nora Butta, Ihosvany Fernández-Bello, Su M Lwin, Miguel Fernández-Arquero, Carlos León, John A McGrath, M Ángeles Vicente, Marcela del Río, Raúl de Lucas, Silvia Sánchez-Ramón, María José Escámez
Journal: British Journal of Dermatology (2023)

Recessive dystrophic epidermolysis bullosa (RDEB) is a blistering genodermatosis due to biallelic loss-of-function variants in the type VII collagen (C7) gene (COL7A1). We report the impact of inflammation/autoimmunity on the gut (and other organs) in the nine children with RDEB recruited to an early-phase clinical trial of systemic cell therapy (NCT04153630). This pilot study provides evidence that autoimmunity may play an important role in sustaining chronic inflammation and the coexistence of coeliac disease, which, in turn, could exacerbate anaemia/malnutrition and progression in RDEB. Testing this hypothesis in a larger cohort including children and adults with RDEB and other epidermolysis bullosa (EB) subtypes is warranted so that targeted interventions may improve outcomes.
Pediatric Hospitalizations at Rural and Urban Teaching and Nonteaching Hospitals in the US, 2009-2019
Authors: JoAnna K. Leyenaar, Seneca D. Freyleue, Mary Arakelyan, David C. Goodman, A. James O’Malley
Journal: JAMA Network Open (2023)

National analyses suggest that approximately 1 in 5 US hospitals closed their pediatric units between 2008 and 2018. The extent to which pediatric hospitalizations at general hospitals in rural and urban communities decreased during this period is not well understood.To describe changes in the number and proportion of pediatric hospitalizations and costs at urban teaching, urban nonteaching, and rural hospitals vs freestanding children's hospitals from 2009 to 2019; to estimate the number and proportion of hospitals providing inpatient pediatric care; and to characterize changes in clinical complexity.This study is a retrospective cross-sectional analysis of the 2009, 2012, 2016, and 2019 Kids' Inpatient Database, a nationally representative data set of US pediatric hospitalizations among children younger than 18 years. Data were analyzed from February to June 2023.Pediatric hospitalizations were grouped as birth or nonbirth hospitalizations. Hospitals were categorized as freestanding children's hospitals or as rural, urban nonteaching, or urban teaching general hospitals.The primary outcomes were annual number and proportion of birth and nonbirth hospitalizations and health care costs, changes in the proportion of hospitalizations with complex diagnoses, and estimated number and proportion of hospitals providing pediatric care and associated hospital volumes. Regression analyses were used to compare health care utilization in 2019 vs that in 2009.The data included 23.2 million (95% CI, 22.7-23.6 million) weighted hospitalizations. From 2009 to 2019, estimated national annual pediatric hospitalizations decreased from 6 425 858 to 5 297 882, as birth hospitalizations decreased by 10.6% (95% CI, 6.1%-15.1%) and nonbirth hospitalizations decreased by 28.9% (95% CI, 21.3%-36.5%). Concurrently, hospitalizations with complex chronic disease diagnoses increased by 45.5% (95% CI, 34.6%-56.4%), and hospitalizations with mental health diagnoses increased by 78.0% (95% CI, 61.6%-94.4%). During this period, the most substantial decreases were in nonbirth hospitalizations at rural hospitals (4-fold decrease from 229 263 to 62 729) and urban nonteaching hospitals (6-fold decrease from 581 320 to 92 118). In 2019, birth hospitalizations occurred at 2666 hospitals. Nonbirth pediatric hospitalizations occurred at 3507 hospitals, including 1256 rural hospitals and 843 urban nonteaching hospitals where the median nonbirth hospitalization volumes were fewer than 25 per year.Between 2009 and 2019, the largest decreases in pediatric hospitalizations occurred at rural and urban nonteaching hospitals. Clinical and policy initiatives to support hospitals with low pediatric volumes may be needed to maintain hospital access and pediatric readiness, particularly in rural communities.
An imperfect world: assessing safety of biological treatments in systemic lupus erythematosus. Comment on the article by Materne et al
Authors: Mia Rodziewicz, Sarah Dyball, Sheilla Achieng, Silke R. Brix, Ben Parker, Ian N. Bruce
Journal: Arthritis & Rheumatology (2023)

Disclosure Form Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Ring1a protects against colitis through regulating mucosal immune system and colonic microbial ecology
Authors: Yashu Wang, Qianru Li, Jiayu Zhang, Pingping Liu, Huaixin Zheng, Lijuan Chen, Zhen Wang, Chen Tan, Min Zhang, Hongxia Zhang, Wenqing Miao, Yuke Wang, Xiaoyan Xuan, Guoqiang Yi, Peng Wang
Journal: Gut Microbes (2023)

Inflammatory bowel disease (IBD) represents a prominent chronic immune-mediated inflammatory disorder, yet its etiology remains poorly comprehended, encompassing intricate interactions between genetics, immunity, and the gut microbiome. This study uncovers a novel colitis-associated risk gene, namely Ring1a, which regulates the mucosal immune response and intestinal microbiota. Ring1a deficiency exacerbates colitis by impairing the immune system. Concomitantly, Ring1a deficiency led to a Prevotella genus-dominated pathogenic microenvironment, which can be horizontally transmitted to co-housed wild type (WT) mice, consequently intensifying dextran sodium sulfate (DSS)-induced colitis. Furthermore, we identified a potential mechanism linking the altered microbiota in Ring1aKO mice to decreased levels of IgA, and we demonstrated that metronidazole administration could ameliorate colitis progression in Ring1aKO mice, likely by reducing the abundance of the Prevotella genus. We also elucidated the immune landscape of DSS colitis and revealed the disruption of intestinal immune homeostasis associated with Ring1a deficiency. Collectively, these findings highlight Ring1a as a prospective candidate risk gene for colitis and suggest metronidazole as a potential therapeutic option for clinically managing Prevotella genus-dominated colitis.We found that PcG protein Ring1a could be a new risk gene for colitis. Ring1a deficiency causes aggravated colitis by regulating the mucosal immune system and colonic microbial ecology.
PTSD Symptoms Among Family Members of Patients With ARDS Caused by COVID-19 After 12 Months
Authors: Nancy Kentish-Barnes, Matthieu Resche-Rigon, Antoine Lafarge, Virginie Souppart, Anne Renet, Frédéric Pochard, Elie Azoulay
Journal: JAMA (2023)

This study compares data on the symptoms of posttraumatic stress disorder (PTSD) among family members of patients with acute respiratory distress syndrome (ARDS) caused by COVID-19 vs non–COVID-19 ARDS.
The Inflamed Niche: A Double-Edged Sword in AML?
Authors: Livia E. Lisi-Vega, Simón Méndez-Ferrer
Journal: Blood Cancer Discovery (2023)

Summary: Although inflammation has long been recognized as a hallmark of many cancers, including acute myeloid leukemia (AML), how it affects individual cells of the tumor microenvironment and their interaction with normal and neoplastic cells is incompletely understood. A comprehensive single-cell transcriptomic analysis of human bone marrow from patients with AML and healthy individuals identified skewing of stem cell and stromal cell populations in AML toward proinflammatory states associated with reduced risk of relapse, paralleling previous findings in mouse models and suggesting that inflamed bone marrow mesenchymal stromal cells might be a double-edged sword in AML by hampering normal hematopoiesis (while AML cells appear comparatively more resilient) but also rendering AML cells more susceptible to chemotherapy or immune attack. See related article by Chen et al., p. 394 (7) .
Empower the Potential of Trastuzumab Deruxtecan with Novel Combinations
Authors: Christian Rolfo, Marzia Del Re, Alessandro Russo
Journal: Clinical Cancer Research (2023)

Summary Trastuzumab deruxtecan (T-DXd) is reshaping the therapeutic landscape of HER2-positive tumors. A recent article reports on the preclinical activity of the combination of T-DXd plus adavosertib, WEE1 kinase inhibitor, which promises to expand the use of this antibody–drug conjugate in HER2-positive tumors with CCNE1 coamplification. See related article by DiPeri et al., p. 4385
Addressing adverse synergies between chemical and biological pollutants at schools—The ‘<scp>SynAir‐G</scp>’ hypothesis
Authors: Nikolaos G. Papadopoulos, Cezmi Akdis, Mubeccel Akdis, Athanasios Damialis, Giuseppina Esposito, Ioana Fergadiotou, Christian Goroncy, Pierre Guitton, Maia Gotua, Kleanthis Erotokritou, Tuomas Jartti, Clare Murray, Athanasios Nenes, Sotirios Nikoletseas, Susetta Finotto, Spyros N. Pandis, Valeria Ramiconi, Angela Simpson, Aki Soudunsaari, Anna Stårbröst, Maria Staiano, Antonio Varriale, Paraskevi Xepapadaki, Torsten Zuberbier, Isabella Annesi‐Maesano
Journal: Allergy (2023)

Abstract While the number and types of indoor air pollutants is rising, much is suspected but little is known about the impact of their potentially synergistic interactions, upon human health. Gases, particulate matter, organic compounds but also allergens and viruses, fall within the ‘pollutant’ definition. Distinct populations, such as children and allergy and asthma sufferers are highly susceptible, while a low socioeconomic background is a further susceptibility factor; however, no specific guidance is available. We spend most of our time indoors; for children, the school environment is of paramount importance and potentially amenable to intervention. The interactions between some pollutant classes have been studied. However, a lot is missing with respect to understanding interactions between specific pollutants of different classes in terms of concentrations, timing and sequence, to improve targeting and upgrade standards. SynAir‐G is a European Commission‐funded project aiming to reveal and quantify synergistic interactions between different pollutants affecting health, from mechanisms to real life, focusing on the school setting. It will develop a comprehensive and responsive multipollutant monitoring system, advance environmentally friendly interventions, and disseminate the generated knowledge to relevant stakeholders in accessible and actionable formats. The aim of this article it to put forward the SynAir‐G hypothesis, and describe its background and objectives.
Q&amp;A: Riccardo Dalla-Favera on Cancer Genetics
Journal: Blood Cancer Discovery (2023)

News in Depth| September 01 2023 Q&A: Riccardo Dalla-Favera on Cancer Genetics Author & Article Information Online ISSN: 2643-3249 Print ISSN: 2643-3230 ©2023 American Association for Cancer Research2023American Association for Cancer Research Blood Cancer Discov (2023) 4 (5): 339–341. https://doi.org/10.1158/2643-3230.BCD-ND2023-0001 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn Email Tools Icon Tools Get Permissions Cite Icon Cite Search Site Article Versions Icon Versions Version of Record September 1 2023 Citation Q&A: Riccardo Dalla-Favera on Cancer Genetics. Blood Cancer Discov 1 September 2023; 4 (5): 339–341. https://doi.org/10.1158/2643-3230.BCD-ND2023-0001 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest Search Advanced Search Cancer as a genetic disease begins with genetic lesions in proto-oncogenes, key regulators of cellular physiology. Discoveries by Riccardo Dalla-Favera, MD, and his team have shaped the modern cancer genetics paradigm, from cloning the first human proto-oncogenes and their cancer-associated variants to elucidating mechanisms of genetic alterations, and mapping the biological processes by which the genetic lesions cause lymphoma. “Most human diseases are cured when you know the mechanism,” Dalla-Favera believes. Toward this aim, his seminal contributions have led to diagnostic and therapeutic advances in lymphoma. Dalla-Favera's discoveries have been recognized by this year's AACR Award for Outstanding Achievement in Blood Cancer Research. As the director of the Institute for Cancer Genetics and professor at Columbia University, New York, Dalla-Favera continues pursuing fundamental questions regarding the genetic mechanisms of cancer through the lens of lymphoma. He shares his perspective on the history, current state, and future avenues of the field... You do not currently have access to this content.
3D‐Printed Osteoinductive Polymeric Scaffolds with Optimized Architecture to Repair a Sheep Metatarsal Critical‐Size Bone Defect
Authors: Charlotte Garot, Sarah Schoffit, Cécile Monfoulet, Paul Machillot, Claire Deroy, Samantha Roques, Julie Vial, Julien Vollaire, Martine Renard, Hasan Ghanem, Hanane El‐Hafci, Adeline Decambron, Véronique Josserand, Laurence Bordenave, Georges Bettega, Marlène Durand, Mathieu Manassero, Véronique Viateau, Delphine Logeart‐Avramoglou, Catherine Picart
Journal: Advanced Healthcare Materials (2023)

The reconstruction of critical-size bone defects in long bones remains a challenge for clinicians. A new osteoinductive medical device is developed here for long bone repair by combining a 3D-printed architectured cylindrical scaffold made of clinical-grade polylactic acid (PLA) with a polyelectrolyte film coating delivering the osteogenic bone morphogenetic protein 2 (BMP-2). This film-coated scaffold is used to repair a sheep metatarsal 25-mm long critical-size bone defect. In vitro and in vivo biocompatibility of the film-coated PLA material is proved according to ISO standards. Scaffold geometry is found to influence BMP-2 incorporation. Bone regeneration is followed using X-ray scans, µCT scans, and histology. It is shown that scaffold internal geometry, notably pore shape, influenced bone regeneration, which is homogenous longitudinally. Scaffolds with cubic pores of ≈870 µm and a low BMP-2 dose of ≈120 µg cm